2 - (phenyl - amino) - 1,3 - diazacyclopentene - (2) substitution products for reducing blood pressure



3,454,701 Patented July 8, 1969 2 (PHENYL AMINO) 1,3 DIAZACYCLOPEN- TENE(2) SUBSTITUTION PRODUCTS FOR RE- DUCING BLOOD PRESSURE Karl Zeile, KarlHeinz Hauptmann, and Helmut Stahle, Ingelheim am Rhein, Germany,assignors to Boehringer Ingelheim G.m.b.H., Ingelheim am Rhein, Germany,a corporation of Germany No Drawing. Continuation-impart of applicationSer. No. 327,806, Dec. 3, 1963, which is a continuation-in-part ofapplication Ser. No. 227,527, Oct. 1, 1962. This application Dec. 21,1965, Ser. No. 515,479 Claims priority, application Germany, Oct. 9,1961,

B 64,319; Oct. 4, 1963, P 144,505 Int. Cl. A61k 27/00 U.S. Cl. 424-273Claims ABSTRACT OF THE DISCLOSURE Therapeutic compositions containing 2-(phenyl-amino)- l,3-diazacyclopentenes-(2) and their non-toxic,pharmacologically acceptable acid addition salts as the activeingredient, as well as to a method of reducing blood pressure andinducing sedation in warm-blooded animals.

This is a continuation-in-part of copending application Ser. No. 327,806filed Dec. 3, 1963, now Patent No. 3,236,857, which in turn is acontinuation-in-part of application Ser. No. 227,527, filed Oct. 1,1962, now Patent No. 3,202,660.

More particularly, the present invention relates to therapeuticcompositions containing a compound selected from the group consisting ofsubstituted Z-(phenylamino -1,3-diazacyclopentanes- (2) R; R: (I)

wherein R and R which may be identical to or different from each other,are each selected from the group consisting of hydrogen, methyl andethyl, and is mono-, di-, or tri-substituted phenyl selected from thegroup consisting of trifiuoromethyl-phenyl,

2,6-dichloro-phenyl,

2-chloro-6-methyl-phenyl,

2-methyl-4-chloro-phenyl,

2-chloro-4-methyl-phenyl,

2-chloro-4-ethyl-phenyl,

2-chloro-6-ethyl-phenyl,

2-chloro-4-tert.butyl-phenyl, 2,6-dichloro-4-methyl-phenyl,2,4-dichloro-6-methyl-phenyl, 2,4-dimethyl-6-chloro-phenyl,2,6-dimethyl-4-chloro-phenyl,

and their non-toxic, pharmacologically acceptable acid addition salts.

The novel compounds embraced by Formula I may be prepared by a varietyof different methods, among which the following have proved to be mostconvenient and efiicient:

Method A By reacting an isothiouronium salt of the formula wherein Z hasthe same meanings as in Formula I, R' is lower alkyl and X is the anionof an acid, preferably the anion of a hydrohalic acid, with analkylenediamine of the formula HNCHCH2-NH2 in I'm (III) wherein R and Rhave the same meanings as in Formula I.

The reaction between the isothiouronium salt II and the alkylenediamineIII is effected by simply heating a mixture of the reactants to about-200 C.

This method leads to satisfactory yields of the desired end product. Inprinciple, the reaction may also be carried out at relatively lowtemperatures (60-140" C.) in the presence of a suitable inert solvent,preferably one which contains polar groups, such as water or loweralkanols; however, it was found that under these conditions longreaction periods must be accepted if good yields are to be achieved. Inthose instances where Z is 2,6-di-substituted phenyl, even prolongedheating in the presence of the particular inert solvent leads only tolow yields of the reaction product. Even a variation of thelast-mentioned process, namely, at elevated pressures, possibly in anatmosphere of an inert gas, does not bring about an increase in theyield.

The isothiouronium salt II required as one of the starting compoundsmay, for example, be prepared in known fashion by heating a thioureacompound obtained from an analogously substituted anilin and ammoniumthiocyanate (Houben-Weyl, vol. 9, page 8-87) with a methyl compound,such as a methyl halide or dimethyl sulfate, in the presence of asuitable inert organic solvent, such as a lower alkanol.

Method B By reacting a primary amine of the formula Z-NH (IV) wherein Zhas the same meanings as in Formula I, with aZ-aIkyl-mercapto-1,3-diazacyclopentene-(2) of the formula R1 R; (V)wherein R and R have the meanings previously defined and R is loweralkyl.

This reaction may be performed in the presence or absence of an inertsolvent. It is important, however, that a sufiiciently high reactiontemperature range be selected in order to drive off the alkylmercaptanreleased by the reaction. In general, the temperature range requiredtherefor is 100-150 0; however, in individual cases it may be necessaryto heat the reaction mixture to about 200 C.

The 2-alkylmercapto-l,3-diazacyclopentenes-(2) V used as startingcompounds in this method may themselves be prepared by alkylation of thecorresponding ethylenethioureas, as described in Organic Syntheses III,394.

Method C By subjecting an N-phenyl-N-(fl-amino-ethyD-thiourea or -ureacompound of the formula H e-NH:

HCN-CNHZ I ia R: Y (VI) wherein R R and Z have the meanings previouslydefined and Y is oxygen or sulfur, to a ring closure reaction bypyrolysis.

The starting compounds VI required for this method may be obtained byreacting a correspondingly substituted phenylisocyanate orphenylisothiocyanate with methylenediamine pursuant to the methoddescribed in Journal of Organic Chemistry, vol. 24 (1959), page 818.

Method D By heating a bis-(2-oxo-1-imidazolidinyl)-phosphine chloride ofthe formula wherein R and R have the meanings previously defined, with aprimary amine of the Formula IV above in the presence of an inertorganic solvent, such as xylene, to a temperature of about 110180 C.

The bis-(2-oxo-l-imidazolidinyl)-phosphine chlorides VII required asstarting materials for this method may themselves be obtained byreacting a correspondingly substituted imidazolidine-l-one withphosphorus pentachloride in the presence of chloroform as an inertsolvent at a temperature of about -40 C., as described in Bull. Soc.Chim., France, 1961, page 2114 et seq.

' The free bases of the Formula I obtained as end products by any of themethods described above may subsequently be transformed into theirnon-toxic, pharmacologically acceptable acid addition salts by customarymethods, for instance, by acidifying a solution of the free base in asuitable organic solvent with the desired acid.

Examples of specific compounds embraced by Formula I which may beprepared by the above described methods are the following:

2-(2,6'-dichlorophenyl) -amino-1,3-diazacyclopentene- (2)2-(2-chloro-4'-methyl-phenyl) -amino-1,3-diazacyclopentene- (2)2-(2'-methyl-4'-chlorophenyl) -amino-1,3 -diazacyclopentene- (2)2-(2-chloro-4-ethy1-phenyl) -amino-1,3-diazacyclopentene-(2)2-(2'-chloro-6'-ethyl-phenyl) -amino-1,3-diazacyclopentene-(2) 2-(2'-chloro-4--tert.butyl-phenyl) -amino- 1,3 -diazacyclopentene-(2) 2-(2-trifluoro-methyl-phenyl) -amino-1,3-diazacyclopentene-(Z) 1-methyl-2-(2,6'-dich1orophenyl) -amino- 1,3-diazacyclopentene- (2) 1-methyl-2-2'-trifiuoro-methyl-phenyl -amino- 1,3-diazacyclopentene- (2)l-methyl-Z- (4'-tert.butyl-2-chlorophenyl) -amino-1,B-diazacyclopentene-(Z) 1-methyl-2- 2'-chloro-6'-ethyl-pheny1) -amino-1,3-diazacyclopentene- (2) 1-methyl-2-( 2'-chloro-4'-methyl-phenyl)-amino- 1,3-diazacyclopentene-(2)2-(2,6-dichlorophenyl)-amino-4-methyl-1,S-diazacyclopentene- 2) 2-(2'-chloro-4'-methyl-phenyl) -amino-4-methyll,3-diazacyclopentene- (2)2- 2'-chloro-6'-ethyl-phenyl -arnino-4-methyl- 1,3-diazacyclopentene-(2)2- (2'-chloro-6'-methyl-phenyl) -amino-1,3 -diazacyclopentene-(2)2-(2',6-dichloro-4-methyl-phenyl) -amino-1,3-diazacyclopentene- (2) 2-(2',4'-dichloro-6'-methyl-phenyl -amino-1,3-diazacyclopentene- (2) I2-(2',4-dimethyl-6'-chlorophenyl)-amino-1,3-diazacyclopentene-(Z) 42-(2',6-dimethyl-4-chlorophenyl) -amino-1,3-diazacyclopentene- (2) Thefollowing examples will further illustrate the present invention andenable others skilled in the art. to understand it more completely. Itshould be understood, however, that the invention is not limited to thespecific examples given below.

EXAMPLE 1.--Preparation of2-(2'-chloro-4'-methylphenyl)-amino-1,3-diazacyclopentene-(2) by MethodA 43 gm. of the thiourea compound (M.P. 124 C.) of the formula obtainedin known fashion from 2-chloro-4-methyl-anilin and ammonium thiocyanateand 20 cc. of methyl iodide were dissolved in 200 cc. of methanol, andthe solution was refluxed for two hours. Thereafter, the solventwasevaporated in vacuo, leaving 73.2 gm. of the isothiouronium hydroiodideof the formula S CH3 as a residue. This isothiouronium salt was admixedwith 20 cc. of ethylenediamine, and the mixture was heated for about 30minutes at 15 0160 C., accompanied by stirring; methyl mercaptan escapedduring that time. Subsequently, the reaction mixture was taken up in hotdilute acetic acid, and the resulting solution was made alkaline with 2N sodium hydroxide. A precipitate formed, which was separated by vacuumfiltration, washed with water and dried. It was identified to be2-(2'-chloro-4-methyl-phenyl)- amino-1,3-diazacyclopentene-(2) of theformula l N-CH:

III-CH: H

NCH1 NHC\ N-CH 01 H CH:

from the isothiouronium salt of the formula I NH S CH:

and propylene-1,2-diamine. The hydrochloride of the base had a meltingpoint of 270-271 C.

(b) 2-(2'-methyl-4'-chlorophenyl)-amino-1,3-diazacyclopentene-(2) of theformula I N--CH2 ClNH-C NCHa having a melting point of 133 C. from theisothiouronium salt of the formula S CH3 and ethylenediamine. Thehydrochloride of the base had a melting point of 199-201 C.

(c) 2-(2'-chloro-4'-ethyl-phenyl)-amino-1,3-diazacyclopentene-(2) of theformula l-CH: H

having a melting point of 124-125" C. from the isothiouronium salt ofthe formula SCH:

and ethylenediamine. The nitrate of the base had a melting point of126-127 C.

EXAMPLE 2.Preparation of 2-(2',6-dichlorophenyl)-amino-1,3-diazacyclopentene-(2) by Method A 16 gm. of the thioureacompound (M.P. 149 C.) of

the formula prepared from 2,6-dichloroaniline (produced by the methoddescribed in Organic Syntheses III, 262263) and ammonium thiocyanate,and 16 gm. of methyl iodide were dissolved in 150 cc. of methanol, andthe solution was refluxed for two and a half hours. The solvent was thenevaporated in vacuo, leaving as a residue 22 gm. of the isothiouroniumhydroiodide (M.P. 170 C.) of the formula I N-C H:

N-CHg Cl I having a melting point of C. The yield was 4.0 gm.

'Its hydrochloride had a melting point of "305 C.

Using a procedure analogous to that described above, the followingadditional substituted phenyla-mino-1,3-diazacyclopentenes-(2) wereprepared;

(a) 2-(2'-chloro-6'-methyl-phenyl)-amino-1,3-diazacyclopentene-(Z) ofthe formula having a melting point of 143-145 C. from the isothiouroniumsalt of the formula and ethylenediamine. The hydrochloride of the basehad a melting point of 217-220 C.

(b) 2-(2-chloro-4'-tert.butyl-phenyl)-amino 1,3 diazacyclopentene-(Z) ofthe formula CH3 /N*CH3 CHa( J NHC/ l CH3 111- H:

from the isothiouronium salt of the formula 01 CH NH 6 OHa- I NH-C HICH3 S CH3 and ethylenediamine. The free base had a melting point of156l58 C., and its nitrate had a melting point of 129 C.

(c) 2-(2'-chloro-6'-ethyl-phenyl)-amino 1,3 diazacyclopentene-(Z) of theformula I N-CH:

I III-CH3 from the isothiouronium salt of the formula I NH NH-C HI andethylenediamine.

Example 3.Preparation of2-(2'-trifluoromethyl-phenyl)-amino-1,3-diazacyclopentene-(2) by MethodA 20.3 gm. of the thiourea compound (M.P. 162l63 C.) prepared in knownfashion from o-trifiuoromethyl-aniline and ammonium thiocyanate, and 10cc. of methyliodide were dissolved in 10 cc. of absolute methanol, andthe resulting solution was refluxed for two and a half hours.Thereafter, the methanol was evaporated in vacuo, leaving as a residue23 gm. of the isothiouronium hydroiodide of the formula S CH3 Theresidue was admixed with 8 cc. of ethylenediamine, and the mixture washeated for about 30 minutes at C., accompanied by stirring.Methylmercaptan-escaped during that time. The reaction mixture wasallowed to cool and was then taken up in dilute hydrochloric acid. Theresulting solution was made alkaline with 2 N sodium hydroxide. Theprecipitate formed thereby, which was identified to be 2-(2-trifluoromethyl-phenyl)-amino- 1,3-diazacyclopentene-(2) of theformula /NCH1 NHC/ lTL-CH: H

was taken up in chloroform, and the resutling solution was admixed withethereal hydrochloric acid, whereby a precipitate formed. Precipitationwas brought to completion by further addition of ether. 6 gm. of2-(2-trifiuoromethylphenyl)-amino-1,3-diazacyclopentene (2)hydrochloride (M.P. 196l98 C.) were obtained.

Example 4.Preparation ofl-methyl-Z-(2',6'-dichlorophenyl)-amino-1,3-diazacyclopentene-(2) byMethod A 16 gm. of the thiourea compound (M.P. 149 C.) obtained in knownfashion from 2,6-dichloro-aniline and ammonium thiocyanate, and 16 gm.of methyl iodide were dissolved in 150 cc. of methanol, and the solutionwas refluxed for two and a half hours. Thereafter, the solvent wasevaporated in vacuo, leaving as a residue 22 gm. of the isothiouroniumhydroiodide (M.P. 170 C.) of the formula S CH: 1

This isothiouronium salt was admixed with 11 cc. of N-methyl-ethylenediamine, and the mixture was heated for about one hour at180 C., accompanied by stirring. Methylmercaptan escaped during thattime. Thereafter, the reaction mixture was taken up in water containinga small amount of dilute hydrochloric acid, and the resulting solutionwas made alkaline with 5 N sodium hydroxide. The precipitate formedthereby was separated by vacuum filtration, washed with water and dried.11 gm. of 1-methyl-2-(2,6'-dichloropheny1)-amino 1,3 diazacyclopentene(2) of the formula having a melting point of 83 C. were obtained.

The nitrate of the base had a melting point of 226 C. and was soluble inwater and ethanol.

Using a procedure analogous to that described above, the followingadditional substituted l-methyl-Z-phenylamino-l,3-diazacyclopentenes-(2)were prepared:

(a) 1-Methyl-2-(2 trifluoromethyl-phenyl)- aminol,3-diazacyclopentene-(2) of the formula N-CH) from the isothiouronium of the formula CF NH andN-methyl-ethylenediamine. The free base had a melting point of 58-61 C.,and its nitrate had a melt ng point of 182-183 C.

8 (b) 1-methyl-2-(2-chloro-4'-methylphenyl) amino-1,3-diazacyclopentene-(2) of the formula N-CH: CH3 NHC\ l from theisothiouronium salt of the formula I NH omQ-un-c m S OH:

and N-methyl-ethylenediamine.

EXAMPLE 5.Preparation of 2 (2.,4' dichloro 6'- methyl-phenyl)-amino 1,3diazacyclopentene-(Z) by Method A A mixture of 12.5 gm. of2,4-dichloro-6-methyl-aniline (prepared by chlorinating o-toluidine inglacial acetic acid and ferric chloride according to Adams, J.A.C.S. 72,2454), cc. of water, 37 cc. of concentrated bydrochloric acid and 368gm. of ammonium thiocyanate was refluxed for seven hours. The thioureacompound of the formula Cl HI This residue was admixed with 7 gm. ofethylenediamine, and the resulting mixture was heated for about one hourat C., accompanied by stirring, during which time methylmercaptanescaped. The reaction mixture was then taken up in 2 N hydrochloricacid, the resulting solution was extracted with chloroform, thechloroform extract solution was filtered through charcoal, and thefiltrate was made weakly alkaline with ammonia. The alkaline solutionwas then extracted with chloroform, the extract solution was dried andfiltered through charcoal, and the chloroform was distilled in vacuofrom the filtrate. The residue was identified to be2-(2',4'-dichloro-6-methylphenyl)-amino-1,3-diazacyclopentene-(2) of theformula The free base was converted into its oxalate by adding anethanolic solution of oxalic acid, extracting the resulting solutionwith ether and evaporating the ether from the extract solution. Afterrecrystallization from a mixture of isopropanol and ether the oxalatehad a melting point of 261263 C. Yield: 9.5 gm.

Using a procedure anologous to that described above,

7 the following additional tri-substituted 2-phenylamin0-1,3-diazacyclopentenes-(2) were prepared:

9 (a) 2-(2,6-dichloro 4' methyl-phenyl)-amino-1,3 diazacyclopentene-(2-,M.P. 156 C., of the formula I N'CH2 N-CHz C1 1 from the rsothlouroniumsalt of the formula OH3- NH-C HI 5 CH3 Cl and ethylenediarnine.

(lb) 2-(2,4-dimethyl 6' chloro-phenyl)-amino-1,3- diazacyclopentene-(2)of the formula N-CHz om-Q-urr-o from the isothiouronium salt of theformula Bil-CH2 I SCHs C1 and ethylenediamine. The oxalate of the basehad a melt ing point of 210 C.

(c) 2-(2',6'-dimethyl 4' chloro-phenyl)-amino-1,3- diazacyclopentene-(Z)of the formula and ethylenediamine. The oxalate of the base had amelting point of 165 C.

The novel phenylamino-l,3-diazacyclopentene-(2) substitution productsaccording to the present invention, that is, the compounds embraced byFormula I above and their non-toxic, pharmacologically acceptable acidaddition salts, have useful pharmacodynamic properties. Moreparticularly, the compounds of the present invention eX- hibit highlyeffective hypotensive and sedative activities and inhibit the secretionof gastric juice, saliva and sweat in warm-blooded animals.

Typical examples of non-toxic, pharmacologically acceptable acidaddition salts of the bases of the Formula I are those formed withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, acetic acid, propionic acid, butyric acid, valeric acid,oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid,lactic acid, tartaric acid, citric acid, malic acid, benzoic acid,phthalic acid, cinnamic acid, salicylic acid, nicotinic acid, 2-furoicacid, ascorbic acid, 8-chloro-theophylline and the like.

The compounds according to the present invention were tested on humansubjects and were found to be highly effective hypotensive agents atdaily dosages of 0.1 to 2 mg. For instance, in healthy, normal humantest subjects a dose of 0.3 mgm. of 2-(2,6'-dichloro-phenyl)-amino-1,3-diazacyclopentene-(2- produced a drop in the systolic blood pressureof up to 35 mm. Hg which had not completely subsided after twenty-fourhours. Approximately the same reduction in blood pressure over the sameperiod of time was achieved by administration of 0.6 mgm. of2-(2-chloro-4-methyl-phenyl)-amino 1,3 diazacyclopentene-(Z) or 0.6 mgm.of 2-(2'-chloro-6'-methylphenyl)-amino-1,3-diazacyclopentene-(2). Inthis connection it should be emphasized that the compounds of thepresent invention reduce the blood pressure even in normal, healthyhumans with normal blood pressure; this is of particular importancebecause most therapeutically applied hypotensive agents either produceno such effect in humans having normal blood pressure or reduce normalblood pressure only if administered at extremely high dose rates.Further, we have found that considerably lower dosages of the compoundsaccording to the invention are required for treatment of high bloodpressure than of most known hypotensive agents. For instance, inoriented clinical tests on high blood pressure patients it was foundthat a dose of only 0.15 mgm. of2-(2,6'-dichlorophenyl)-amino-1,3-diazacyclopentene-(2) produces anaverage reduction of 45 mm. Hg in the systolic blood pressure.

A further advantage of the compounds according to the present inventionis their low toxicity. For instance, the LD of2-(2',6-dichlorophenyl)-amino-1,3-diazacyclopentene-(2) in mice is 390mgm./kg. per 0s and 127.5 mgm./kg. SC; for 2-(2-chloro-6-methyl-phenyl)-amino-1,3-diazacyclopentene-(2) it is mgm./ kg. per 0s and 102 mgm./ kg.S.C.; and for2-(2'-chloro-4-methylphenyl)-amino-1,3-diazacyclopentene-(2) it is 320mgm./ kg. per 0s and 42.5 mgm./kg. S.C. These values indicate anextraordinarily favorable therapeutic ratio which assures the safety ofthe novel compounds in therapeutic applications.

In addition, the compounds of the present invention exhibit effectivesedative activities which are already detectable at the hypotensivedosages, but become clearly observable at slightly higher dosages of 0.2to 5 mg. Thus, a dose of 0.2-0.4 mgm. of 2-(2',6-dichlorophenyl)-amino-1,3-diazacyclopentene-(2) produced sedation which lasted for sixhours, and a dose of 1-2 mgm. produced sedation which persisted forabout thirty hours. 0.6-1 mgm. of2-(2-chloro-4'-methyl-phenyl)-amino-1,3-diazacyclopentene-(Z) inducedsedation lasting for five to eight hours, and after administration of2.4 mgm. of this compound the test subjects slept for about 19 hours.Similar effects were achieved with 2-(2-chloro-6'-methyl-phenyl)-amino-1,3-diazacyclopentene-(2).

The compounds of the present invention induce a sound and long-lastingsleep from which the patients may, however, be fully awakened at anytime. Thus, the novel compounds offer a substantial advantage overcustomary sleep-inducing sedatives, especially over the barbiturates;for instance, a moderate overdose of such customary seda tives whichinduces sleep for twenty to thirty hours invariably leads tounconsciousness almost resembling a state of anesthesia for the firstfew hours, from which the patient can be awakened into a dazed state forbrief periods of time only by strong stimulations.

For therapeutic application the compounds of the present invention areadministered perorally, rectally or parenterally as active ingredientsin dosage unit compositions, that is, in compositions consistingessentially of an inert, physiologically compatible carrier havinguniformly distributed therein one dosage unit of the active ingredient.One dosage unit of the compounds of the present invention is from 0.025to 10 mgm.

The following examples illustrate a few dosage unit compositionscomprising a compound of the present invention as the active ingredient.The parts are parts by weight unless otherwise specified.

1 1 EXAMPLE 6 Tablets The tablet composition is compounded from thefollowing ingredients:

The individual ingredients are admixed in customary fashion, and themixture is pressed into tablets weighing 90 mgm. each. An individualtablet then contains 0.1 mgm. of the active ingredient.

EXAMPLE 7 Demineralized water q.s.ad 100 parts by vol.

The various solid ingredients are dissolved in the demineralized water,and the solution is filled into 100 cc. bottles. Twenty drops of thesolution (1 cc.) contain 0.2 mgm. of the active ingredient.

EXAMPLE 8 Hypodermic solution The solution is compounded from thefollowing ingredients:

Parts 2,(2-chloro-6'-methyl-phenyl)-amino-1,3-

diazacyclopentene-(Z) nitrate 0.05 Sodium chloride 18.0 Distilled waterq.s.ad 2000 parts by vol.

The active ingredient and the sodium chloride are dissolved in a portionof the distilled water, and the solution is then diluted with distilledwater to the required volume. The solution is then filtered until freefrom fibrous material and is filled into 2 cc. ampules, which are thensterilized and sealed. Each ampule contains 0.05 mgm. of the activeingredient.

EXAMPLE 9 Rectal suppositories The suppository composition is compoundedfrom the following ingredients:

Parts 2- (2',6'-dichlorophenyl)-arnino-1,3-

diazacyclopentene-(2) 0.4 Lactose 244.6

Cocoa butter q.s.ad 1700 parts by vol.

The cocoa butter is melted, the active ingredient and the lactose areadded, the mixture is allowed to cool slightly and is then homogenized.Thereafter, the composition is poured into cooled suppository moldsholding 1700 mgm. each. Every individual suppository contains 0.4 mgm.of the active ingredient.

Although the above dosage unit composition examples illustrate onlycertain specific compounds of the present invention as activeingredients, it should be understood that any of the other compoundsembraced by Formula I or their non-toxic acid addition salts may besubstituted in the compositions for those specifically illustrated.Similarly, the amount of the active ingredient in the illustrativecompositions may be varied within the indicated dosage range to meetparticular requirements and depending upon whether only a hypotensivee'ifect or also a sleep-inducing sedative elfect is to be achieved. Inthe case of hypodermic solutions the active ingredient is preferablyprovided in the form of a non-toxic acid addition salt.

Pharmacological data Varying doses of the test compounds wereadministered intravenously (v. femoralis) to test rabbits under urethaneanaesthesia. The variations in mm. Hg in the blood pressure of therabbits was determined by a mercury monometer connected to their carotidartery. The results are summarized in the following table:

Blood Number pressure of Dosage change in Test compound tests /kg. mm.of Hg CLAIMED COMPOSITIONS 2-[2,6'-dichlorophenyl]-amino-1,3- 26 3 -10.0 diazacyclopentene-(2)-hydro 10 18. G chloride. 30 37. l 50. 02-[2'-chloro-4-methy1phenyl]- 8 1 l. 5 amino-1,3 diazacyclopentene- 3 -8(2)-hydrochloride. z113 --11.2g 2-[2'-chloro-6-methy1phenyl]- 9 1 4amino1,3-diazacyc1opentene- 3 -3. 5 (2)-hydrochloride. 10 11 30 23 10025 2-[2,4-dichloro-6-methyl-pheny1]- 6 10 8 amino-1,3-diazacyclopentene-30 -6 (2)-oxalate. 100 -10 1000 -1t$ PRIOR am or BLOOM2-[2,4'-dichlorophenyl]-arnino-l,3- 10 1 +4 diazacyclopentene-(2)-hydro-3 +12 chloride. 10 0 30 +8 100 +23. 5 2-[2',5-diehlorophenyH-amino-l,3-9 10 +28 diazacyc1opentene-(2)-hydro- 30 +37 chloride. 100 +40. 52-[2-chlorophenyl]-amino-1,3- 6 1 +7. 5 diazaeyclopentene-(2)-hydro- 10+6 chloride. 100 +16 The test data of the above table shows that thecompositions of the invention have a clear definite hypotensive (bloodpressure decrease) efiect while the prior art products of Bloom possessjust the opposite activity, namely, hypertensive or blood pressureincreasing effect.

We claim:

1. A pharmacodynamic composition consisting essentially of an inert,physiologically compatible carrier and from 0.025 to 10 mgm. of acompound selected from the group consisting of2-phenylamino-1,3-diazacyclopentene- (2) substitution products of theformula NCH ZNHC/ W R1 R: wherein R and R are each selected from thegroup consisting of hydrogen, methyl and ethyl, and Z is selected fromthe group consisting of 2,6-dichlorophenyl, 2-trifluoromethyl-phenyl,2-chloro-6-methy1-phenyl, 2-met-hyl-4-chloro-phenyl,2-chloro-4-methyl-phenyl, 2-chloro-4-ethyl-phenyl,2-chloro-6-ethyl-phenyl, 2-chloro-4-tert.butyl-phenyl,2,6-dichloro-4-methyl-phenyl, 2,4-dichloro--methyl-phenyl,2,4dimethyl-6-chloro-phenyl, and 2,6-dimethyl-4-chloro-phenyl, and theirnon-toxic pharmacologically acceptable acid addition Salts.

2. A composition of claim 1 wherein Z is 2,6-dichlorop enyl and R and Rare hydrogen.

3. A composition of claim 1 wherein Z is 2-chloro-4- methylphenyl and Rand R are hydrogen,

4. A composition of claim 1 wherein Z is 2-ch1oro-6- methylphenyl and Rand R are hydrogen.

5. A composition of claim 1 wherein Z is 2,4-dichloro- 6-methylpheny1and R and R are hydrogen.

6. The method of reducing the blood pressure in warmblooded animals,which comprises administering to the said animals an eifective amount ofa compound selected from the group consisting ofZ-phenyl-amino-l,3-diazacyclopentene-(2) substitution products of theformula /NCH3 ZNHO f? R1 R2 wherein R and R are each selected from thegroup consisting of hydrogen, methyl and ethyl, and Z is selected fromthe group consisting of 2,6-dichlorophenyl, Z-trifluoromethyl-phenyl,2-chlo-ro-6-methyl-phenyl, 2-methyl-4-chloro-phenyl,2-chloro-4-methyl-phenyl, 2-chloro-4-ethyl-phenyl,2-chloro-6-ethyl-phenyl,

1 4 2-chlor0-4-tert.butyl-phenyl, 2,6-dichloro-4-methyl-phenyl,2,4-rlichloro-6-methyl-phenyl, 2,4-dimethyl-6-chloro-phenyl,2,6-dimethyl-4-chloro-phenyl,

and

References Cited UNITED STATES PATENTS 2,899,426 8/1959 Bloom 260309.62,899,434 8/ 1959 Bloom 26025 6.4 3,202,660 8/1965 Zeile et a1 260-2543,236,857 2/1966 Zeile et a1. 260309.6

FRANK CACCIAPAGLIA, IR., Primary Examiner.

I. D. GOLDBERG, Assistant Examiner.

